Abstract:

The present invention provides processes and intermediates useful in the
preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a
serotonin (5-HT) receptor agonist that is useful in the treatment or
prophylaxis of, for example, central nervous system disorders, such as
obesity.

Claims:

2. The process according to claim 1, further comprising the step of
isolating said 2-(4-chlorophenyl)ethyl bromide.

3. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted in the absence of an
added solvent.

4. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted by adding said
hydrogen bromide to said 2-(4-chlorophenyl)ethanol.

5. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted by adding the
hydrogen bromide as a gas below the surface of the
2-(4-chlorophenyl)ethanol.

6. The process according to claim 1, wherein said reacting hydrogen
bromide with said 2-(4-chlorophenyl)ethanol is conducted by adding said
hydrogen bromide as a gas to said 2-(4-chlorophenyl)ethanol.

7. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from
about 25.degree. C. to about 110.degree. C.

8. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from
about 60.degree. C. to about 100.degree. C.

9. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from
about 70.degree. C. to about 90.degree. C.

10. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from
about -1.00 bar to about +2.00 bar.

11. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from
about -1.00 bar to about +0.50 bar.

12. The process according to claim 1, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from
about -0.85 bar to about +0.37 bar.

13. The process according to claim 2, wherein said isolating comprises
separating a water co-product from said 2-(4-chlorophenyl)ethyl bromide.

14. The process according to claim 2, wherein after said isolating step,
2-(4-chlorophenyl)ethyl bromide has a purity of about 95% or greater as
determined by HPLC.

15. The process according to claim 2, wherein after said isolating step,
2-(4-chlorophenyl)ethyl bromide has a purity of about 97% or greater as
determined by HPLC.

16. A process for preparing 2-chloro-N-(4-chlorophenethyl)propan-1-amine
hydrochloride comprising the steps:a) reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol to form 2-(4-chlorophenyl)ethyl bromide;b)
reacting said 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol to
form 1-(4-chlorophenethylamino)propan-2-ol; andc) reacting said
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride to form
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride.

17. The process according to claim 16, wherein said reacting hydrogen
bromide with said 2-(4-chlorophenyl)ethanol is conducted in the absence
of an added solvent.

18. The process according to claim 16, wherein said reacting hydrogen
bromide with said 2-(4-chlorophenyl)ethanol is conducted by adding said
hydrogen bromide to said 2-(4-chlorophenyl)ethanol.

19. The process according to claim 16, wherein said reacting hydrogen
bromide with said 2-(4-chlorophenyl)ethanol is conducted by adding said
hydrogen bromide as a gas to said 2-(4-chlorophenyl)ethanol.

20. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from
about 25.degree. C. to about 110.degree. C.

21. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from
about 60.degree. C. to about 100.degree. C.

22. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a temperature from
about 70.degree. C. to about 90.degree. C.

23. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from
about -1.00 bar to about +2.00 bar.

24. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from
about -1.00 bar to about +0.50 bar.

25. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol is conducted at a pressure from
about -0.85 bar to about +0.37 bar.

26. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol, produces said
2-(4-chlorophenyl)ethyl bromide with a purity of about 95% or greater as
determined by HPLC.

27. The process according to claim 16, wherein said reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol, produces said 2-(4-chlorophenyl)
ethyl bromide with a purity of about 97% or greater as determined by
HPLC.

28. The process according to claim 16, wherein said reacting
2-(4-chlorophenyl) ethyl bromide with 1-aminopropan-2-ol is conducted by
the addition of 2-(4-chlorophenyl)ethyl bromide to 1-aminopropan-2-ol.

29. The process according to claim 16, wherein said reacting
2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol is conducted by
the addition of 2-(4-chlorophenyl)ethyl bromide to 1-aminopropan-2-ol at
a rate such that 1-(bis(4-chlorophenethyl)amino)propan-2-ol is formed in
an amount less than about 10% compared to
1-(4-chlorophenethylamino)propan-2-ol as determined by HPLC.

30. The process according to claim 16, wherein said reacting
2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol is conducted by
the addition of 2-(4-chlorophenyl)ethyl bromide to 1-aminopropan-2-ol at
a rate such that 1-(bis(4-chlorophenethyl)amino)propan-2-ol is formed in
an amount less than about 5% compared to
1-(4-chlorophenethylamino)propan-2-ol as determined by HPLC.

31. The process according to claim 16, wherein said reacting
2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol is conducted in
the presence of a molar excess of 1-aminopropan-2-ol compared to
2-(4-chlorophenyl)ethyl bromide.

32. The process according to claim 16, wherein said reacting
2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol is conducted at a
temperature from about 60.degree. C. to about 95.degree. C.

33. The process according to claim 16, wherein said reacting
2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol is conducted at a
temperature from about 75.degree. C. to about 90.degree. C.

34. The process according to claims 16, wherein said reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted
in the presence of a solvent.

35. The process according to claim 34, wherein said solvent comprises
toluene.

36. The process according to claim 16, wherein said reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted
in the presence of dimethylacetamide.

37. The process according to claim 16, wherein said reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted
at a temperature from about 55.degree. C. to about 70.degree. C.

38. The process according to claim 16, wherein said reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride is conducted
at a temperature from about 60.degree. C. to about 65.degree. C.

39. The process according to claim 16, further comprising a step of
separating a water co-product from said 2-(4-chlorophenyl)ethyl bromide
after step a) and prior to step b).

40. The process according to claim 16, wherein after step a) the resulting
mixture is used in step b) without substantial purification.

41. The process according to claim 16, further comprising a step of
removing 1-aminopropan-2-ol from the mixture after step b) and prior to
step c).

42. The process according to clam 41, wherein said removing
1-aminopropan-2-ol from the mixture after step b) is conducted by the
steps comprising:adding water and an immiscible organic solvent to the
mixture after step b) to form a biphasic mixture comprising an aqueous
phase and an organic phase;mixing said biphasic mixture and subsequently
allowing to separate into said aqueous phase and said organic phase;
andremoving said aqueous phase from said organic phase.

44. The process according to claim 42, wherein said immiscible organic
solvent is toluene.

45. The process according to claim 16, further comprising a step of
crystallizing said 2-chloro-N-(4-chlorophenethyl)propan-1-amine
hydrochloride after step c).

46. The process according to claim 45, wherein said crystallizing said
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride is conducted
in the presence of a mixture comprising a C1-C6 alcohol.

47. The process according to claim 45, wherein said crystallizing said
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride is conducted
in the presence of a mixture comprising isopropanol.

48. The process according to claim 16, wherein steps a), b) and c) are
conducted without substantial purification.

49. The process according to claim 16, wherein said reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride, produces
said 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride with a
purity of about 95% or greater as determined by HPLC.

50. The process according to claim 16, wherein said reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride, produces
said 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride with a
purity of about 98% or greater as determined by HPLC.

Description:

FIELD OF THE INVENTION

[0001]The present invention provides processes and intermediates useful in
the preparation of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a serotonin
(5-HT) receptor agonist that is useful in the treatment or prophylaxis
of, for example, central nervous system disorders, such as obesity.

BACKGROUND OF THE INVENTION

[0002]Serotonin (5-HT) neurotransmission plays an important role in
numerous physiological processes both in neurological and in psychiatric
disorders. For example, 5-HT has been implicated in the regulation of
feeding behavior. 5-HT is believed to work by inducing a feeling of
fullness or satiety so eating stops earlier and fewer calories are
consumed. It has been shown that a stimulatory action of 5-HT on the
5HT2C receptor plays an important role in the control of eating.
Furthermore, stimulation of the 5HT2C receptor has also been shown
to play an important role in the anti-obesity effect of d-fenfluramine.
As the 5-HT2C receptor is expressed in high density in the brain
(notably in the limbic structures, extrapyramidal pathways, thalamus and
hypothalamus specifically in the PVN and DMH, and predominantly in the
choroid plexus) and is expressed in low density or is absent in
peripheral tissues, a selective 5-HT2C receptor agonist can be a
more effective and safe anti-obesity agent. Also, 5-HT2C knockout
mice are overweight with cognitive impairment and susceptibility to
seizure. Thus, the 5HT2C receptor is recognized as a well-accepted
receptor target for the treatment of obesity, psychiatric disorders, and
other disorders.

[0003]In view of the growing demand for compounds useful in the treatment
of disorders related to the 5-HT2C receptor,
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine has emerged has
an important new compound. Accordingly, new and more efficient routes
leading to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and
intermediates related thereto are needed. The processes and compounds
described herein help meet these and other needs.

SUMMARY OF THE INVENTION

[0004]The processes and intermediates of the present invention are useful
in preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
having Formula (I):

##STR00001##

[0005]This compound is useful in the treatment of 5-HT2C receptor
associated disorders, such as, obesity, and is disclosed in PCT patent
publication, WO2003/086303.

[0006]Some embodiments of the present invention disclose processes for
preparing 2-(4-chlorophenyl)ethyl bromide comprising the steps:
[0007]reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form a
reaction mixture comprising the 2-(4-chlorophenyl)ethyl bromide; and
[0008]isolating the 2-(4-chlorophenyl)ethyl bromide from the reaction
mixture.

[0009]Some embodiments of the present invention disclose processes for
preparing 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride
comprising the steps: [0010]a) reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol to form 2-(4-chlorophenyl)ethyl bromide;
[0011]b) reacting said 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol to form 1-(4-chlorophenethylamino)propan-2-ol; and
[0012]c) reacting said 1-(4-chlorophenethylamino)propan-2-ol with thionyl
chloride to form 2-chloro-N-(4-chlorophenethyl)propan-1-amine
hydrochloride.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0013]The processes and intermediates of the present invention are useful
in the preparation of the therapeutic agent
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, including,
salts and crystal forms thereof. The compound
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, including,
salts and crystal forms are disclosed in PCT patent publications,
WO2003/086306 and WO2006/069363.

[0014]Certain processes for the preparation of compounds of Formula (I)
and salts thereof are disclosed in PCT patent publications, WO2005/019179
and WO2007/120517.

[0015]Intermediates useful in the preparation of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, HCl salts and
crystal forms thereof, include 2-(4-chlorophenyl)ethyl bromide and
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride.

[0016]Several improvements and advantages have now been discovered for the
preparation of each and are described herein.

Conversion of the Commercially Available Compound
2-(4-chlorophenyl)ethanol to 2-(4-chlorophenyl)ethyl bromide with the Use
of HBr.

[0017]In some embodiments, 2-(4-chlorophenyl)-ethyl bromide can be
prepared from the commercially available compound,
2-(4-chlorophenyl)ethanol, according to the process depicted in Synthetic
Scheme 1.

##STR00002##

Accordingly, in some embodiments, the invention discloses processes for
preparing 2-(4-chlorophenyl)ethyl bromide comprising reacting hydrogen
bromide with 2-(4-chlorophenyl)ethanol to form 2-(4-chlorophenyl)ethyl
bromide.

[0018]In some embodiments, the present invention discloses processes for
preparing 2-(4-chlorophenyl)ethyl bromide comprising the steps:
[0019]reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form a
reaction mixture comprising the 2-(4-chlorophenyl)ethyl bromide; and
[0020]isolating the 2-(4-chlorophenyl)ethyl bromide from the reaction
mixture.

[0021]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted in the absence of an added
solvent. The phrase "absence of an added solvent" is intended to mean
that none or no substantial amount of solvent is added to the reaction
(e.g. the reaction can be conducted "neat" in the absence of solvent). It
is understood that during the reaction an equivalent amount of water is
formed together with 2-(4-chlorophenyl)ethyl bromide and that this water
so formed is not considered as a solvent but merely as a co-product for
purposes of this definition. It is further understood that any impurity
present in 2-(4-chlorophenyl)ethanol in an amount of about 5% or less as
determined by HPLC does not constitute "an added solvent" for the
purposes of this definition.

[0022]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted by adding the hydrogen bromide to
the 2-(4-chlorophenyl)ethanol.

[0023]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted by adding the hydrogen bromide as
a gas to the 2-(4-chlorophenyl)ethanol.

[0024]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted by adding the hydrogen bromide as
a gas above the surface of the 2-(4-chlorophenyl)ethanol. In some
embodiments, the presure above the surface of the
2-(4-chlorophenyl)ethanol is about +2 bar to about ambient presure. In
some embodiments, the presure above the surface of the
2-(4-chlorophenyl)ethanol is about +1.65 bar to about +0.5 bar.

[0025]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted by adding the hydrogen bromide as
a gas below the surface of the 2-(4-chlorophenyl)ethanol.

[0026]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a temperature from about
25° C. to about 110° C.

[0027]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a temperature from about
60° C. to about 100° C.

[0028]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a temperature from about
70° C. to about 90° C.

[0029]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar
to about +2.00 bar.

[0030]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar
to about +0.50 bar.

[0031]In some embodiments, the reacting of hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a pressure from about -0.85 bar
to about +0.37 bar.

[0032]In some embodiments, isolating comprises separating the water
co-product from the 2-(4-chlorophenyl)ethyl bromide.

[0033]In some embodiments, after the isolating step,
2-(4-chlorophenyl)ethyl bromide has a purity of about 95% or greater as
determined by HPLC. In some embodiments, after the isolating step,
2-(4-chlorophenyl)ethyl bromide has a purity of about 97% or greater as
determined by HPLC. The term "HPLC" refers to High Performance Liquid
Chromatography. In some embodiments, "HPLC" refers to Reversed-Phase High
Performance Liquid Chromatography. In some embodiments, "HPLC" refers to
Normal-Phase High Performance Liquid Chromatography.

Conversion of the Commercially Available Compound
2-(4-chlorophenyl)ethanol to
2-chloro-N-(4-chlorophenethyl)propan-1-amine.

[0034]In some embodiments, 2-chloro-N-(4-chlorophenethyl)propan-1-amine
hydrochloride can be prepared from 2-(4-chlorophenyl)ethanol according to
the process depicted in Synthetic Scheme 2.

##STR00003##

[0035]In some embodiments, the present invention discloses processes for
preparing 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride
comprising the steps: [0036]a) reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol to form 2-(4-chlorophenyl)ethyl bromide;
[0037]b) reacting the 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol to form 1-(4-chlorophenethylamino)propan-2-ol; and
[0038]c) reacting the 1-(4-chlorophenethylamino)propan-2-ol with thionyl
chloride to form 2-chloro-N-(4-chlorophenethyl)propan-1-amine
hydrochloride.

[0039]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted in the absence of an added
solvent.

[0040]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted by adding the hydrogen bromide to
the 2-(4-chlorophenyl)ethanol.

[0041]In some embodiments, reacting hydrogen bromide with said
2-(4-chlorophenyl)ethanol is conducted by adding said hydrogen bromide as
a gas to said 2-(4-chlorophenyl)ethanol.

[0042]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a temperature from about
25° C. to about 110° C.

[0043]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a temperature from about
60° C. to about 100° C.

[0044]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a temperature from about
70° C. to about 90° C.

[0045]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar
to about +2.00 bar.

[0046]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a pressure from about -1.00 bar
to about +0.50 bar.

[0047]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol is conducted at a pressure from about -0.85 bar
to about +0.37 bar.

[0048]In some embodiments, reacting hydrogen bromide with
2-(4-chlorophenyl)ethanol, produces 2-(4-chlorophenyl)ethyl bromide with
a purity of about 95% or greater as determined by HPLC. In some
embodiments, reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol,
produces 2-(4-chlorophenyl)ethyl bromide with a purity of about 97% or
greater as determined by HPLC. In some embodiments, "HPLC" refers to
Reversed-Phase High Performance Liquid Chromatography. In some
embodiments, "HPLC" refers to Normal-Phase High Performance Liquid
Chromatography.

[0049]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted by the addition of
2-(4-chlorophenyl)ethyl bromide to 1-aminopropan-2-ol.

[0050]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted by the addition of
2-(4-chlorophenyl)ethyl bromide to 1-aminopropan-2-ol at a rate such that
1-(bis(4-chlorophenethyl)amino)propan-2-ol is formed in an amount less
than about 10% compared to 1-(4-chlorophenethylamino)propan-2-ol as
determined by HPLC.

[0051]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted by the addition of
2-(4-chlorophenyl)ethyl bromide to 1-aminopropan-2-ol at a rate such that
1-(bis(4-chlorophenethyl)amino)propan-2-ol is formed in an amount less
than about 5% compared to 1-(4-chlorophenethylamino)propan-2-ol as
determined by HPLC. The chemcial structure for
1-(bis(4-chlorophenethyl)amino)propan-2-ol is shown below:

##STR00004##

1-(bis(4-chlorophenethyl)amino)propan-2-ol

[0052]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted in the presence of a molar excess of
1-aminopropan-2-ol compared to 2-(4-chlorophenyl)ethyl bromide.

[0053]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted in the presence of about 5 molar excess
of 1-aminopropan-2-ol compared to 2-(4-chlorophenyl)ethyl bromide.

[0054]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted at a temperature from about 60° C.
to about 95° C.

[0055]In some embodiments, reacting 2-(4-chlorophenyl)ethyl bromide with
1-aminopropan-2-ol is conducted at a temperature from about 75° C.
to about 90° C.

[0056]In some embodiments, reacting 1-(4-chlorophenethylamino)propan-2-ol
with thionyl chloride is conducted in the presence of a solvent. In some
embodiments, the solvent is an aromatic hydrocarbon. In some embodiments,
the solvent comprises toluene. In some embodiments, the solvent is
toluene.

[0057]In some embodiments, reacting 1-(4-chlorophenethylamino)propan-2-ol
with thionyl chloride is conducted in the presence of dimethylacetamide
(also referred to as DMA).

[0058]In some embodiments, reacting 1-(4-chlorophenethylamino)propan-2-ol
with thionyl chloride is conducted in the presence of dimethylformamide
(also referred to as DMF).

[0059]In some embodiments, reacting 1-(4-chlorophenethylamino)propan-2-ol
with thionyl chloride is conducted at a temperature from about 55°
C. to about 70° C.

[0060]In some embodiments, reacting 1-(4-chlorophenethylamino)propan-2-ol
with thionyl chloride is conducted at a temperature from about 60°
C. to about 65° C.

[0061]In some embodiments, the process further comprises a step of
separating a water co-product from the 2-(4-chlorophenyl)ethyl bromide
after step a) and prior to step b).

[0062]In some embodiments, wherein after step a) the resulting mixture is
used in step b) without substantial purification.

[0063]In some embodiments, the process further comprises a step of
removing 1-aminopropan-2-ol from the mixture after step b) and prior to
step c). In some embodiments, the removing of 1-aminopropan-2-ol from the
mixture after after step b) is conducted by the steps comprising:
[0064]adding water and an immiscible organic solvent to the mixture after
step b) to form a biphasic mixture comprising an aqueous phase and an
organic phase; [0065]mixing the biphasic mixture and subsequently
allowing to separate into the aqueous phase and the organic phase; and
[0066]removing the aqueous phase from the organic phase.

[0069]In some embodiments, the process further comprises a step of
crystallizing the 2-chloro-N-(4-chlorophenethyl)propan-1-amine
hydrochloride after step c). In some embodiments, crystallizing the
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride is conducted
in the presence of a mixture comprising a C1-C6 alcohol. In
some embodiments, crystallizing the
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride is conducted
in the presence of a mixture comprising isopropanol.

[0070]In some embodiments, steps a), b) and c) are conducted without
substantial purification and in doing so steps a), b) and c) are
considered to be "telescoped" steps. The phrase "without substantial
purification" is intended to mean that little or no substantial
purification is utilized, such as, chromatography (reverse-phase
chromatography, normal-phase chromatography, flash, HPLC, MPLC, etc.),
distillation (vacuum or atmospheric) of product, etc. It is understood
that, 1) the mere removal of water by phase separation, where the water
was either a co-product of the reaction or physically added; 2) the
removal of a volatile solvent (i.e. a liquid with a boiling point of
about 150° C. or less at atmospheric pressure); and 3)
recrystallization and crystallization, are not considered substantial
purification steps for purposes of this definition.

[0071]In some embodiments, after reacting
1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride, produces
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride with a purity
of about 95% or greater as determined by HPLC. In some embodiments, after
reacting 1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride, the
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride with a purity
of about 98% or greater as determined by HPLC. In some embodiments,
"HPLC" refers to Reversed-Phase High Performance Liquid Chromatography.
In some embodiments, "HPLC" refers to Normal-Phase High Performance
Liquid Chromatography.

[0072]The invention will be described in greater detail by way of specific
examples. The following examples are offered for illustrative purposes,
and are not intended to limit the invention in any manner. Those of skill
in the art will readily recognize a variety of noncritical parameters
which can be changed or modified to yield essentially the same results.

EXAMPLES

Example 1

Preparation of 2-(4-chlorophenyl)ethyl bromide from
2-(4-chlorophenyl)ethanol

[0073]In a 1 L pressure vessel, 4-chlorophenylethanol (412.8 g, 2636 mmol)
was stirred and heated to an internal temperature of ˜91° C.
The system was held under reduced pressure (˜-0.98 bar) for
˜2 min. Hydrogen bromide gas was gradually charged into the
pressure vessel and the reaction was stirred at an internal pressure
between +0.69 and +1.65 bar for 135 min. The vessel was allowed to slowly
vent to a caustic scrubber and flushed with nitrogen gas for ˜5
min. Conversion to the bromide was found to be 4.27% by HPLC. The
reaction mixture was allowed to cool to ambient temperature overnight
under nitrogen. The mixture was then heated once more in an oil bath set
at 96° C. and the vessel was evacuated. The vessel was gradually
filled with hydrogen bromide gas and stirred at an internal pressure
between +1.38 and +1.65 bar for 2 h. Conversion to the bromide was found
to be 92.67% by HPLC. The reaction was held at a bath temperature of
96° C. at atmospheric pressure for 45 min. The vessel was then
evacuated and slowly backfilled with hydrogen bromide gas over 15 min to
+1.38 bar. After stirring for a further 2.5 h at +1.24 to +1.38 bar, the
vessel was vented to the caustic scrubber and held at a bath temperature
of 96° C. in closed system at atmospheric pressure. Conversion to
the bromide was found to be 99.49% by HPLC with a peak area purity of
98.71%.

[0074]In order to test stability and impurity formation, the pressure
vessel was then evacuated and gradually back filled with hydrogen bromide
gas to an internal pressure of +1.03 bar. The dark brown suspension was
allowed to stir at +1.03 bar at a bath temperature of 96° C. After
15 h the internal pressure had risen to +2.41 bar and the vessel was
vented to the caustic scrubber, purged with nitrogen, and allowed to cool
to ambient temperature. The peak area purity was found to be 96.06%. The
reaction mixture was transferred to a seperatory funnel and allowed to
separate at room temp. The upper product phase was washed with water (412
mL) in 2 portions to leave a milky beige suspension (563.4 g) with an
HPLC peak area purity of 99.29%.

Example 2

Preparation of 2-(4-chlorophenyl)ethyl bromide from
2-(4-chlorophenyl)ethanol

[0075]2-(4-Chlorophenyl)ethanol (1600 kg, 10.22 mol) was heated with
stirring in a jacketed reactor to 70° C. After the reactor had
been evacuated to -0.85 bar and sealed, hydrogen bromide gas was bubbled
into the liquid 2-(4-chlorophenyl)ethanol while allowing the heat of
reaction to warm the stirred reaction mixture to 90° C. The
hydrogen bromide gas addition was continued sufficiently slowly to
maintain the stirred reactor contents at 90° C. with reactor
jacket cooling. When 1072 kg (13.25 mol) of hydrogen bromide gas had been
added, the reactor pressure was +0.37 bar, and HPLC analysis of the
reaction mixture's upper organic phase revealed percentage peak areas of
96.0 and 1.63 for 2-(4-chlorophenyl)ethyl bromide and
2-(4-chlorophenyl)ethanol respectively. The stirred reaction mixture was
vented to a caustic scrubber and cooled to 30° C. The reaction
mixture was then allowed to stand for 130 min to permit phase separation.
The lower aqueous HBr phase (490 kg) was drained at 29° C. To
remove as much residual hydrogen bromide as possible before the final
water wash, the stirred upper product phase was sparged with nitrogen at
atmospheric pressure for 77 minutes at 30° C., evacuated to -0.85
bar, sparged with nitrogen again and maintained under reduced pressure
for one hour at 30° C. Water (445 kg) was then added, and the
resulting stirred mixture was sparged with nitrogen at 30° C. for
2 h. The reactor contents were then allowed to stand for 3 h to permit
phase separation. The milky lower product phase was drained from the
clear upper aqueous phase. The upper aqueous phase weighed 465 kg. The
lower product phase weighed 2190 kg (97.7% yield not corrected for assay)
and was found to have an HPLC peak area purity of 98.0%.

[0076]In a 65 mL glass pressure vessel, 4-chlorophenylethanol (32.725 g,
209 mmol) was warmed to between 90 and 100° C. The vessel was
charged with hydrogen bromide gas and the mixture was stirred at +1.38 to
+1.93 bar for 4.5 h. The pressure was released and the reaction showed
99.18% conversion by HPLC. The mixture was allowed to cool to room
temperature to leave 2-(4-chlorophenyl)ethyl bromide as a brown liquid
(53.735 g).

[0077]Without purification, this was then added with stirring to a 100 mL
round-bottom flask containing 1-aminopropan-2-ol (83 mL, 1046 mmol) at
85° C. The clear yellow mixture was stirred at 85 to 95° C.
for 2 h, at which time LCMS indicated 100% conversion. The reaction was
allowed to cool to room temperature overnight and then warmed to
75° C. to form a yellow oil. Water (23 mL) was added followed by
toluene (96 mL) maintaining the temperature between 70 and 75° C.
and the resulting mixture was stirred at this temperature for 15 min. The
mixture was allowed to separate and the lower aqueous layer was extracted
with toluene. The combined organic layers were concentrated to leave
1-(4-chlorophenethylamino)propan-2-ol as a yellow oil.

[0078]The oil was suspended in toluene (179 mL) and warmed to 50°
C. to dissolve. N,N-Dimethylacetamide (5.88 mL, 62.7 mmol) was added
followed by thionyl chloride (19.38 mL, 266 mmol) dropwise while
maintaining the internal temperature at <60° C. On completion
of the addition, the reaction was stirred at between 60 and 65° C.
for 4 h. LCMS indicated 100% conversion to the chloride. The reaction was
allowed to cool to room temperature and filtered. The cake was washed
with toluene and dried on the filter overnight. The dried solids were
suspended in isopropanol (85.8 mL) and water (7.2 mL) and the stirred
mixture was heated to reflux for 1 h then cooled to between 12 and
15° C. over 1 h. The mixture was stirred at this temperature for 1
h, cooled further to 0 to 3° C. and stirred for an additional 1 h.
The slurry was filtered and the cake was washed with isopropanol and
dried under reduced pressure at 70° C. to leave the title compound
as an off white solid (37.719 g, 67.2%; 100% peak area purity by HPLC).

Preparation of 2-(4-chlorophenyl)ethyl bromide from
2-(4-chlorophenyl)ethanol

[0104]The quantities in the following procedure are normalized to 1.00 kg
of the starting material 2-(4-chlorophenyl)ethanol. The yield shown below
is the average from four separate production runs using 1600-2400 kg of
the starting material 2-(4-chlorophenyl)ethanol, the following quantities
and volume ratios.

[0105]To a reactor was charged 2-(4-chlorophenyl)ethanol (1.00 kg, 1.00
mol equivalent). The reactor contents were stirred and heated to
70° C. and purged with several cycles of evacuation and refilling
with nitrogen. After the final evacuation, HBr gas was sparged into the
stirred reactor contents (subsurface) and the temperature of the reaction
mixture was allowed to increase from about 70° C. to about
90° C. The HBr gas was continued into the stirred reaction mixture
at a sufficient rate to maintain the reactor pressure at or below 20 psig
and the temperature of the reactor contents at about 85-95° C.
with reactor jacket cooling. After the HBr gas uptake slows, samples of
the crude reaction mixture were obtained to determine conversion of
2-(4-chlorophenyl)ethanol to 2-(4-chlorophenyl)ethyl bromide. After the
conversion was achieved [2-(4-chlorophenyl)ethanol<2% by HPLC peak
area, typically one hour after addition of 0.669 kg (1.296 mol equiv.) of
HBr gas] the reactor was vented to atmospheric pressure through a caustic
scrubber and cooled to approximately 30° C. The reaction mixture
was allowed to stand for about two hours to provide two phases. The lower
aqueous HBr byproduct phase (0.281 kg) was drained to waste. The
resulting crude product was sparged with nitrogen gas at 30° C.
and atmospheric pressure for about 75 minutes to remove as much residual
hydrogen bromide as possible before the final water wash. The reactor was
evacuated and the nitrogen sparging of nitrogen was continued through the
stirred crude product at 30° C. for about an hour while continuing
to pull full vacuum. To the resulting crude product was charged with
water (0.278 kg) the contents stirred at 30° C. for 15 minutes.
The stirring was stopped and the phases were allowed to separate at
30° C. over 2 to 3 hours. The lower product phase,
2-(4-chlorophenyl)ethyl bromide, 1.375 kg, 98.1% yield not corrected for
assay, 98.0 area % pure by HPLC, was separated from the upper aqueous
phase (0.296 kg).

[0106]Observered times required to achieve ≧98.4% conversion of
2-(4-chlorophenyl)ethanol to 2-(4-chlorophenyl)ethyl bromide ranged from
approximately 6 hours at 413 g laboratory scale to approximately 35 hours
at 2400 kg scale. At 2400 kg scale, the rate-limiting factor was
vaporization of HBr from the supply cylinders, not gas-liquid mass
transfer in the reactor.

[0107]Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from the
foregoing description. Such modifications are also intended to fall
within the scope of the appended claims.

Patent applications in class Halogen attached directly or indirectly to the acyclic carbon or chain by acyclic nonionic bonding with no amino nitrogen between the halogen and the aryl ring or ring system

Patent applications in all subclasses Halogen attached directly or indirectly to the acyclic carbon or chain by acyclic nonionic bonding with no amino nitrogen between the halogen and the aryl ring or ring system